Growth differentiation factor 15 alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy.

Growth differentiation factor 15 (GDF15) is a peptide with utility in obesity, as it decreases appetite and promotes weight loss. Because obesity increases the risk for type 2 diabetes (T2D) and cardiovascular disease, it is imperative to understand the cardiovascular actions of GDF15, especially since elevated GDF15 levels are an established biomarker for heart failure. As weight loss should be encouraged in the early stages of obesity-related prediabetes/T2D, where diabetic cardiomyopathy is often present, we assessed whether treatment with GDF15 influences its pathology.

Liraglutide alleviates experimental diabetic cardiomyopathy in a PDH-dependent manner.

Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist used for the treatment of T2D, has been shown to alleviate diabetic cardiomyopathy (DbCM) in experimental T2D, which was associated with increased myocardial glucose oxidation. To determine whether this increase in glucose oxidation is necessary for cardioprotection, we hypothesized that liraglutide's ability to alleviate DbCM would be abolished in mice with cardiomyocyte-specific deletion of pyruvate dehydrogenase (PDH; Pdha1CM-/- mice), the rate-limiting enzyme of glucose oxidation. Male Pdha1CM-/- mice and their α-myosin heavy chain Cre expressing littermates (αMHCCre mice) were subjected to experimental T2D via 10 weeks of high-fat diet supplementation, with a single low-dose injection of streptozotocin (75 mg/kg) provided at week 4.

Loss of muscle PDH induces lactic acidosis and adaptive anaplerotic compensation via pyruvate-alanine cycling and glutaminolysis.

Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation that links glycolysis-derived pyruvate with the tricarboxylic acid (TCA) cycle. Although skeletal muscle is a significant site for glucose oxidation and is closely linked with metabolic flexibility, the importance of muscle PDH during rest and exercise has yet to be fully elucidated. Here, we demonstrate that mice with muscle-specific deletion of PDH exhibit rapid weight loss and suffer from severe lactic acidosis, ultimately leading to early mortality under low-fat diet provision.

Ketone ester administration improves glycemia in obese mice.

During periods of prolonged fasting/starvation, the liver generates ketones [i.e., β-hydroxybutyrate (βOHB)] that primarily serve as alternative substrates for ATP production.